Melanoma has an intrinsic susceptibility to metastasize and is generally resistant to medical treatment. Because of the increasing burden of this potentially lethal disease, improved methods of prevention, early diagnosis and treatment of melanoma are expected to be of increasing importance. Somatic mutations in the oncogenes BRAF and NRAS have been found in a substantial proportion of primary invasive melanomas. Despite recent progress in identification of these mutations, their population-based frequency in melanoma is still unknown and a critical gap exists in the knowledge base regarding their association with heterogeneity, precursor lesions, risk, and prognosis in melanoma. In this study, the population-based frequency and mutational spectrum of NRAS and BRAF mutations in primary human melanoma will be determined in 300 consecutive cases of invasive primary melanoma with first diagnosis in the year 2000 in North Carolina. Detailed epidemiologic and pathology information compiled for these cases will allow the determination of the association of NRAS and BRAF mutational phenotypes with histologic subtype, potential precursor lesions, prognostic indicators and risk factors. NRAS and BRAF somatic mutations will be detected and characterized using the highly sensitive technique of single strand conformational polymorphism analysis combined with direct manual sequencing of PCR products. The data derived from this study is expected to clarify the role of NRAS and BRAF in the development, progression and heterogeneity of melanoma, leading to better prevention, early detection, classification and treatment of this disease. Elucidation of how these mutations might arise in relationship to environmental and hereditary factors should result in more evidence-based recommendations for risk factor avoidance. In addition, understanding how mutations arise in relationship to precursors should provide information regarding which potential precursors should be removed and insight into methods of early detection. This study is also expected to lead to identification of new chemotherapeutic targets and more efficient testing of inhibitors for NRAS and BRAF signaling, which have recently been developed.